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Akshata Anand Korgaonkar
Biomedical Engineering Program
M.S. 2010, New Jersey Institute of Technology, Newark, NJ
Thesis Advisor: Viji Santhakumar, Ph.D.
Department of Pharmacology, Physiology & Neuroscience
Thursday, April 28, 2016
2:00 P.M., MSB Room H609
Concussive brain injury results in neuronal degeneration, microglial activation, enhanced excitability, synaptic loss and plasticity in the hippocampal dentate gyrus, increasing the risk for epilepsy and memory dysfunction. Endogenous molecules released during injury can activate innate immune responses including toll-like receptor 4 (TLR4). My published work conducted as part of this thesis identified that enhanced neuronal expression of the innate immune receptor, Toll-like Receptor 4 (TLR4) contributes to increase in dentate excitability after TBI (Li et al., 2015). Unexpectedly, TLR4 agonists reduced excitability in uninjured rats. These findings lead to the hypothesis that TLR4 signaling engages distinct molecular effectors in the control and injured brain and that TLR4-signaling in the injured brain augments dentate excitability and contributes to memory dysfunction and enhanced risk for seizures. The results presented in this thesis demonstrate that glial signaling is necessary for TLR4 modulation of neuronal excitability in controls but not after brain injury suggesting that the divergent neurophysiological effects of TLR4 in the normal and injured brain are mechanistically separable. Examination of the role of TNFα in TLR4 signaling revealed contribution of TNFα to TLR4 effects in both control and injured brains. Together, these data have identified a novel role for TNFα in neuronal TLR4 signaling in the injured brain. As anticipated, brain injury resulted in chronic enhancement of seizure susceptibility and spontaneous epilepsy. Additionally, brain injury transiently compromised working memory function. Early, but not delayed, treatment with a TLR4 antagonist, after injury reversed the increase in seizure susceptibility and improved working memory function. However, TLR4 antagonist treatment increased the risk for seizures and compromised working memory performance in uninjured rats. Together these findings indicate that TLR4 signaling contributes to long-term neurological disorders after brain injury by cellular mechanisms that may be distinct from the normal physiological function of TLR4. Thus, selectively targeting the processes underlying pathological TLR4 signaling may be efficacious in reducing epilepsy and memory impairments after brain injury.